Optimizing Silk Nanoparticle Assembly with Potassium Ions: Effects on Physicochemical Properties and Encapsulation Efficiency.

Silk fibroin is a promising biomaterial for nanocarrier-based drug delivery due to its biocompatibility, biodegradability, and tunable mechanical properties. In addition, the silk protein is amenable to various processing strategies, offering flexibility for optimizing particle characteristics. Emerging evidence highlights that metal ions can modulate silk conformation and structure in the silk gland, as well as influencing self-assembly, potentially impacting silk nanoparticle fabrication. Our previous study highlighted the potential of Ca(2+) in silk nanoparticle fabrication. However, other metal ions in the silk gland influence silk fibroin behavior too. Here, we investigate how potassium ions (K(+)), with similar abundance to Ca(2+) in the silkworm gland, influence silk nanoparticle formation as modulators of self-assembly and material properties, aiming to produce nanoparticles with distinct physicochemical profiles. We show that K(+) enhances silk assembly, increases nanoparticle size, alters surface charge (zeta potential), and boosts production yield, thereby minimizing silk wastage during silk nanoparticle preparation. Potassium ions also significantly improve payload encapsulation efficiency, making K(+) inclusion valuable for a range of drug-loading applications. The resulting silk nanoparticles exhibit reduced toxicity and inflammatory response, highlighting their promise as safe and effective nanocarrier candidates for drug delivery. Our findings establish K(+) as a fundamental yet powerful tool for tuning silk nanoparticle properties to meet pharmaceutical needs.